title: Pancreatic digestive enzyme blockade in the small intestine prevents insulin resistance in hemorrhagic shock.
abstract: Hemorrhagic shock is associated with metabolic defects, including hyperglycemia and insulin resistance, but the mechanisms are unknown. We recently demonstrated that reduction of the extracellular domain of the insulin receptor by degrading proteases may lead to a reduced ability to maintain normal plasma glucose values. In shock, transfer of digestive enzymes from the lumen of the intestine into the systemic circulation after breakdown of the intestinal mucosal barrier causes inflammation and organ dysfunction. Suppression of the digestive enzymes in the lumen of the intestine with protease inhibitors is effective in reducing the level of the inflammatory reactions. To determine the degree to which blockade of digestive enzymes affects insulin resistance in shock, rats were exposed to acute hemorrhagic shock (mean arterial pressure of 30 mmHg for 2 h) at which time all shed blood volume was returned. Digestive proteases in the intestine were blocked with a serine protease inhibitor (tranexamic acid in polyethylene glycol and physiological electrolyte solution), and the density of the insulin receptor was measured with immunohistochemistry in the mesentery microcirculation. The untreated rat without enzyme blockade had significantly attenuated levels of insulin receptor density as compared with control and treated rats. Blockade of the digestive proteases after 60 min of hypotension in the lumen of the small intestine led to a lesser decrease in insulin receptor density compared with controls without protease blockade. Glucose tolerance test indicates a significant increase in plasma glucose levels 2 h after hemorrhagic shock, which are reduced to control values in the presence of protease inhibition in the lumen of the intestine. The transient reduction of the plasma glucose levels after an insulin bolus is significantly attenuated after shock but is restored when digestive enzymes in the lumen of the intestine are blocked. These results suggest that in hemorrhagic shock elevated microvascular extracellular digestive enzyme activity causes insulin receptor dysfunction, hyperglycemia, and reduced ability to regulate blood glucose values.
authors.affiliation: Microcirculation Laboratory, Department of Bioengineering, Institute of Engineering in Medicine, University of California-San Diego, La Jolla, California.
authors.forename: Frank A
authors.initials: FA
authors.lastname: DeLano
authors.forename: Geert W
authors.initials: GW
authors.lastname: Schmid-Schönbein
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007333:Insulin Resistance / Q000502:physiology*; D007421:Intestine, Small / Q000201:enzymology*; D008297:Male; D010179:Pancreas / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000097:blood; D057057:Serine Proteases / Q000502:physiology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D012771:Shock, Hemorrhagic / Q000097:blood / Q000201:enzymology / Q000503:physiopathology*; D013152:Splanchnic Circulation / Q000502:physiology; D014148:Tranexamic Acid / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D015842:Serine Proteinase Inhibitors; D014148:Tranexamic Acid; D011972:Receptor, Insulin; D057057:Serine Proteases